Defining effective anti-HIV immune responses is a major unsolved problem in HIV vaccine development. We have previously shown that immunization with virulence-attenuated SHPV89.6 protects 60% of rhesus macaques against vaginal challenge with pathogenic SIVmac239. Thus, the SHIV89.6 vaccine/SIVmac239 challenge system provides us with the opportunity to define immune correlates of protection by comparing immune responses in vaccinated-protected and vaccinated-unprotected animals. As live attenuated viruses persistently replicate in the host, and it is conceivable that the more robust protection observed with this compared to other vaccine strategies is the result of both attenuated lentivirus-induced innate antiviral immune responses and anamnestic T and B cell responses. Importantly, innate effector cells are present at mucosal surfaces, the primary entry site for HIV/SIV, they can directly inhibit virus replication, and they are critical for the induction of adaptive antiviral responses. Despite evidence that innate effector mechanisms contribute to attenuated-lentivirus vaccine-mediated protection and contribute to the control of HIV-1 replication in long-term non-progressor patients, there are no studies examining the complex interaction between innate and adaptive antiviral immune responses in HTV/SIV infection and vaccine-mediated protection. Thus, the goal of Aim 1 is to define differences in host immune responses in vaccinated-protected and vaccined-unprotected animals and to determine which host immune responses are associated with SHIV89.6-mediated protection. The results of this study will form the basis for Aims 2-6 in this application as we will then confirm and define the relative contribution of multiple effector mechanisms identified in Aim 1 to vaccine-mediated anti-SIV immunity by either depleting distinct effector cell populations (Aims 3 and 4) or by using pharmacological interventions (Aims 2, 5, and 6) to interfere with distinct immune mechanisms. Further, by selectively manipulating innate or adaptive effector responses, the interplay and dependence of both mechanisms on each other can be demonstrated. If we can identify innate immune mechanisms important in attenuated-lentivirus induced vaccine-mediated protection against vaginal SIV challenge, we can then try to exploit and stimulate these responses in "conventional" vaccine strategies through the use of adjuvants or immunomodulatory therapies to increase overall vaccine efficacy.